Aranesp

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Aranesp

CLINICAL PHARMACOLOGY

Mechanism Of Action

Aranesp stimulates erythropoiesis by the same mechanism
as endogenous erythropoietin.

Pharmacodynamics

Increased hemoglobin levels are not generally observed
until 2 to 6 weeks after initiating treatment with Aranesp.

Pharmacokinetics

Adult Patients with CKD

The pharmacokinetics of Aranesp were studied in patients
with CKD receiving or not receiving dialysis and cancer patients receiving
chemotherapy.

Following intravenous administration of Aranesp to
patients with CKD receiving dialysis, Aranesp serum concentration-time profiles
were biphasic, with a distribution half-life of approximately 1.4 hours and a
mean terminal half-life (t1/2) of 21 hours. The t1/2 of Aranesp was
approximately 3-fold longer than that of epoetin alfa when administered
intravenously.

Following subcutaneous administration of Aranesp to
patients with CKD (receiving or not receiving dialysis), absorption was slow
and Cmax occurred at 48 hours (range: 12 to 72 hours). In patients with CKD
receiving dialysis, the average t1/2 was 46 hours (range: 12 to 89 hours), and
in patients with CKD not receiving dialysis, the average t1/2 was 70 hours
(range: 35 to 139 hours). Aranesp apparent clearance was approximately 1.4
times faster on average in patients receiving dialysis compared to patients not
receiving dialysis. The bioavailability of Aranesp in patients with CKD
receiving dialysis after subcutaneous administration was 37% (range: 30% to
50%).

Pediatric Patients with CKD

Aranesp pharmacokinetics was studied in 12 pediatric
patients (age 3 to 16 years) with CKD receiving or not receiving dialysis.
Following a single intravenous or subcutaneous Aranesp dose, Cmax and t½ were
similar to those obtained in adult patients with CKD on dialysis. Following a
single subcutaneous dose, the average bioavailability was 54% (range: 32% to
70%), which was higher than that obtained in adult patients with CKD on
dialysis.

Adult Cancer Patients

Following the first subcutaneous dose of 6.75 mcg/kg
(equivalent to 500 mcg for a 74-kg patient) in patients with cancer, the mean t1/2
was 74 hours (range: 24 to 144 hours) and Cmax was observed at 71 hours (range:
28 to 120 hours). When administered on a once every 3 week schedule, 48-hour
postdose Aranesp levels after the fourth dose were similar to those after the
first dose.

Over the dose range of 0.45 to 4.5 mcg/kg Aranesp
administered intravenously or subcutaneously on a once weekly schedule and 4.5
to 15 mcg/kg administered subcutaneously on a once every 3 week schedule,
systemic exposure was approximately proportional to dose. No evidence of
accumulation was observed beyond an expected less than 2-fold increase in blood
levels when compared to the initial dose.

Reproductive And Developmental Toxicology

When Aranesp was administered intravenously during
organogenesis to pregnant rats (gestational days 6 to 15) and rabbits
(gestational days 6 to 18), no evidence of direct embryotoxic, fetotoxic, or
teratogenic outcomes were observed at the doses tested, up to 20 mcg/kg/day.
This animal dose level of 20 mcg/kg/day is approximately 20-fold higher than the
clinical recommended starting dose, depending on the patient's treatment
indication. The only adverse effect observed was a slight reduction in fetal
weight, which occurred only at doses causing exaggerated pharmacological
effects in both the rat and rabbit dams (1 mcg/kg/day and higher). No
deleterious effects on uterine implantation were seen in either species.

No significant placental transfer of Aranesp was observed
in rats; placental transfer was not evaluated in rabbits.

In a peri/postnatal development study, pregnant female
rats were treated intravenously with Aranesp day 6 of gestation through day 23
of lactation at 2.5 mcg/kg and higher every other day. Pups of treated mothers
had decreased fetal body weights, which correlated with slight increases in the
incidences of fetal death, as well as delayed eye opening and delayed preputial
separation. The offspring (F1 generation) of the treated rats were observed
postnatally; rats from the F1 generation reached maturity and were mated; no
Aranesp-related effects were apparent for their offspring (F2 generation
fetuses).

Clinical Studies

Clinical studies in the nephrology and
chemotherapy-induced anemia clinical programs are designated with the prefixes
“N” and “C”, respectively.

Patients With Chronic Kidney Disease

Patients with chronic kidney disease on dialysis: ESA
effects on rates of transfusion

In early clinical studies conducted in CKD patients on
dialysis, ESAs have been shown to reduce the use of RBC transfusions. These
studies enrolled patients with mean baseline hemoglobin levels of approximately
7.5 g/dL and ESAs were generally titrated to achieve a hemoglobin level of
approximately 12 g/dL. Fewer transfusions were given during the ESA treatment
period when compared to a pre-treatment interval.

In the Normal Hematocrit Study, the yearly transfusion
rate was 51.5% in the lower hemoglobin group (10 g/dL) and 32.4% in the higher
hemoglobin group (14 g/dL).

Patients with chronic kidney disease not on dialysis:
ESA effects on rates of transfusion

In TREAT, a randomized, double-blind trial of 4038
patients with CKD and type 2 diabetes not on dialysis, a post-hoc analysis
showed that the proportion of patients receiving RBC transfusions was lower in
patients administered Aranesp to target a hemoglobin of 13 g/dL compared to the
control arm in which Aranesp was administered intermittently if hemoglobin
concentration decreased to less than 9 g/dL (15% versus 25%, respectively). In
CHOIR, a randomized open-label study of 1432 patients with CKD not on dialysis,
use of an ESA to target a higher (13.5 g/dL) versus lower (11.3 g/dL)
hemoglobin goal did not reduce the use of RBC transfusions. In each trial, no
benefits occurred for the cardiovascular or end-stage renal disease outcomes.
In each trial, the potential benefit of ESA therapy was offset by worse
cardiovascular safety outcomes resulting in an unfavorable benefit-risk profile
[see WARNINGS AND PRECAUTIONS].

ESA Effects on quality of life

Aranesp use has not been demonstrated in controlled
clinical trials to improve quality of life, fatigue, or patient well-being.

ESA Effects on rates of death and other serious
cardiac adverse events

Three randomized outcome trials (Normal Hematocrit Study
[NHS], Correction of Anemia with Epoetin Alfa in Chronic Kidney Disease
[CHOIR], and Trial of Darbepoetin Alfa in Type 2 Diabetes and CKD [TREAT]) have
been conducted in patients with CKD using Epogen/PROCRIT/Aranesp to target
higher vs. lower hemoglobin levels. Though these trials were designed to
establish a cardiovascular or renal benefit of targeting higher hemoglobin
levels, in all 3 studies, patients randomized to the higher hemoglobin target
experienced worse cardiovascular outcomes and showed no reduction in
progression to ESRD. In each trial, the potential benefit of ESA therapy was
offset by worse cardiovascular safety outcomes resulting in an unfavorable
benefit-risk profile [see WARNINGS AND PRECAUTIONS].

Other ESA trials

Two studies evaluated the safety and efficacy of the de
novo use of Aranesp for the correction of anemia in adult patients with CKD,
and 3 studies (2 in adults and 1 in pediatric patients) assessed the ability of
Aranesp to maintain hemoglobin concentrations in patients with CKD who had been
receiving other recombinant erythropoietins.

De Novo Use of Aranesp

Once Weekly Aranesp Starting Dose

In 2 randomized, open-label studies, Aranesp or epoetin
alfa was administered for the correction of anemia in patients with CKD who had
not been receiving prior treatment with exogenous erythropoietin. Study N1
evaluated CKD patients receiving dialysis; Study N2 evaluated patients not
requiring dialysis. In both studies, the starting dose of Aranesp was 0.45
mcg/kg administered once weekly. The starting dose of epoetin alfa was 50
Units/kg 3 times weekly in Study N1 and 50 Units/kg twice weekly in Study N2.
When necessary, dosage adjustments were instituted to maintain hemoglobin in
the study target range of 11 to 13 g/dL. (Note: The recommended hemoglobin target
range is lower than the target range of these studies [see DOSAGE AND
ADMINISTRATION].) The primary efficacy endpoint was the proportion of
patients who experienced at least a 1 g/dL increase in hemoglobin concentration
to a level of at least 11 g/dL by 20 weeks (Study N1) or 24 weeks (Study N2).
The studies were designed to assess the safety and effectiveness of Aranesp but
not to support conclusions regarding comparisons between the 2 products.

In Study N2, the primary efficacy endpoint was achieved
by 93% (95% CI: 87%, 97%) of the 129 patients treated with Aranesp and 92% (95%
CI: 78%, 98%) of the 37 patients treated with epoetin alfa. The mean increase
in hemoglobin from baseline through the initial 4 weeks of Aranesp treatment
was 1.38 g/dL (95% CI: 1.21 g/dL, 1.55 g/dL).

Once Every 2 Week Aranesp Starting Dose

In 2 single-arm studies (N3 and N4), Aranesp was
administered for the correction of anemia in CKD patients not receiving
dialysis. In both studies, the starting dose of Aranesp was 0.75 mcg/kg
administered once every 2 weeks.

In Study N4 (study duration of 24 weeks), the hemoglobin
goal (hemoglobin concentration of 11 to 13 g/dL) was achieved by 85% (95% CI:
77%, 93%) of the 75 patients treated with Aranesp.

Conversion from Other Recombinant Erythropoietins

Two studies of adults (N5 and N6) and 1 study in
pediatric patients (N7) were conducted in patients who had been receiving other
recombinant erythropoietins for treatment of the anemia due to CKD. The studies
compared the abilities of Aranesp and other erythropoietins to maintain
hemoglobin concentrations within a study target range of 9 to 13 g/dL in adults
and 10 to 12.5 g/dL in pediatric patients. (Note: The recommended hemoglobin
target is lower than the target range of these studies [see DOSAGE AND
ADMINISTRATION].) Patients who had been receiving stable doses of other
recombinant erythropoietins were randomized to Aranesp or continued with their
prior erythropoietin at the previous dose and schedule. For patients randomized
to Aranesp, the initial weekly dose was determined on the basis of the previous
total weekly dose of recombinant erythropoietin.

Adult Patients

Study N5 was a double-blind study in which 169
hemodialysis patients were randomized to treatment with Aranesp and 338
patients continued on epoetin alfa. Study N6 was an open-label study in which
347 patients were randomized to treatment with Aranesp and 175 patients were
randomized to continue on epoetin alfa or epoetin beta. Of the patients
randomized to Aranesp, 92% were receiving hemodialysis and 8% were receiving
peritoneal dialysis.

Pediatric Patients

Study N7 was an open-label, randomized study conducted in
the United States in pediatric patients from 1 to 18 years of age with CKD
receiving or not receiving dialysis. Eighty-one patients with hemoglobin
concentrations that were stable on epoetin alfa received darbepoetin alfa
(subcutaneously or intravenously), and 42 patients continued to receive epoetin
alfa at the current dose, schedule, and route of administration. Patients
received darbepoetin alfa once weekly if previously receiving epoetin alfa 2 or
3 times weekly or once every other week if previously receiving epoetin alfa
weekly. A median weekly dose of 0.41 mcg/kg darbepoetin alfa (25th, 75th
percentiles: 0.25, 0.82 mcg/kg) was required to maintain hemoglobin in the
study target range.

Cancer Patients Receiving Chemotherapy

The safety and efficacy of Aranesp was assessed in two
multicenter, randomized studies in patients with anemia due to the effect of
concomitantly administered cancer chemotherapy. Study C1 was a randomized
(1:1), placebo-controlled, double-blind, multinational study conducted in 314
patients where Aranesp was administered weekly. Study C2 was a randomized
(1:1), double-blind, double-dummy, active-controlled, multinational study
conducted in 705 patients where Aranesp was administered either every week or every
3 weeks. Efficacy was demonstrated by a statistically significant reduction in
the proportion of patients receiving RBC transfusions among patients who were
on study therapy for more than 28 days.

Study C1

Study C1 was conducted in anemic patients (hemoglobin
≤ 11 g/dL) with non-small cell lung cancer or small cell lung cancer who
were scheduled to receive at least 12 weeks of a platinum-containing
chemotherapy regimen. Randomization was stratified by tumor type and region
(Australia vs. Canada vs. Europe). Patients received Aranesp 2.25 mcg/kg or
placebo as a weekly subcutaneous injection commencing on the first day of the
chemotherapy cycle. Efficacy was determined by a reduction in the proportion of
patients who received RBC transfusions between week 5 (day 29) and end of
treatment period (12 weeks) in the subset of 297 randomized patients (148
Aranesp and 149 placebo) who were on-study at the beginning of study week 5.
All 297 patients were white, 72% were male, 71% had non-small cell histology, and
the median age was 62 years (range: 36 to 80). A significantly lower proportion
of patients in the Aranesp arm received RBC transfusions during week 5 to the
end of treatment compared to patients in the placebo arm (crude percentages:
26% vs. 50%; p < 0.001, based on a comparison of the difference in
Kaplan-Meier proportions using the Cochran-Mantel-Haenszel strata-adjusted
Chi-square test).

Study C2

Study C2 was conducted in anemic patients (hemoglobin
< 11 g/dL) with non-myeloid malignancies receiving chemotherapy.
Randomization was stratified by region (Western vs. Central/Eastern Europe),
tumor type (lung and gynecological vs. others), and baseline hemoglobin ( <
10 vs. ≥ 10 g/dL); all patients received double-dummy placebo and either
Aranesp 500 mcg every 3 weeks or Aranesp 2.25 mcg/kg weekly subcutaneous
injections for 15 weeks. Only 1 patient was non-white, 55% were female, and the
median age was 60 years (range: 20 to 86). One hundred seven patients (16%) had
lung or gynecological cancer while 565 (84%) had other tumor types. In both
treatment schedules, the dose was reduced by 40% of the previous dose if
hemoglobin level increased by more than 1 g/dL in a 14-day period.

Efficacy was determined by a comparison of the proportion
of patients who received at least 1 RBC transfusion between week 5 (day 29) and
the end of treatment. Three hundred thirty-five patients in the every 3 week
dosing arm and 337 patients in the weekly dosing arm remained on study through
or beyond day 29 and were evaluable for efficacy. Two hundred thirty-eight
patients (71%) in the every 3-week arm and 261 patients (77%) patients in the
weekly arm required dose reductions. Twenty-three percent (95% CI: 18%, 28%) of
patients in the every 3-week treatment schedule and 28% (95% CI: 24%, 34%) in
the weekly schedule received at least 1 RBC transfusion. The observed
difference in the RBC transfusion rates (every 3 week minus weekly) was -5.8%
(95% CI: -12.4%, 0.8%).

Study C3

Lack of Efficacy in Improving Survival

Study C3 was conducted in patients required to have a
hemoglobin concentration ≥ 9 g/dL and ≤ 13 g/dL with previously
untreated extensive-stage small cell lung cancer (SCLC) receiving platinum and
etoposide chemotherapy. Randomization was stratified by region (Western Europe,
Australia/North America, and rest of world), Eastern Cooperative Oncology Group
(ECOG) performance status (0 or 1 vs. 2), and lactate dehydrogenase (below vs.
above the upper limit of normal). Patients were randomized to receive Aranesp
(n = 298) at a dose of 300 mcg once weekly for the first 4 weeks, followed by
300 mcg once every 3 weeks for the remainder of the treatment period or placebo
(n = 298).

This study was designed to detect a prolongation in
overall survival (from a median of 9 months to a median of 12 months). For the
final analysis, there was no evidence of improved survival (p = 0.43, log-rank
test).

Last reviewed on RxList: 1/27/2014
This monograph has been modified to include the generic and brand name in many instances.